The present invention, in some embodiments thereof, relates to compounds, compositions and methods for treating disorders associated with pathological hyperplasia, metaplasia, dysplasia and neoplasia (oncoplasia) tissues, such as, for example, skin and visible mucosal tumors and lesions and internal neoplasms.
Neoplasia is a general term used to describe abnormal proliferation of cells (such as malignant neoplasia). This abnormal proliferation may be a result of many disorders (such as a viral infection or cancerogenesis) and usually causes a lump or tumor. Neoplastic tissue may be characterized as being viral, benign, pre-malignant or malignant.
Cell proliferation is regulated by a balance between growth-promoting proto-oncogenes and growth-constraining tumor-suppressor genes. Oncogenesis can be caused by genetic alterations to the genome that result in the mutation of those cellular elements that govern the interpretation of cellular signals, such as potentiation of proto-oncogene activity or inactivation of tumor suppression. It is believed that the interpretation of these signals ultimately influences the growth and differentiation of a cell, and that misinterpretation of these signals can result in neoplastic growth (neoplasia).
Current methods of treating neoplasia include surgery, laser surgery, photodynamic therapy, cryotherapy, chemotherapy and radiation. Chemotherapy involves administration of compounds having antitumor activity, such as alkylating agents, antimetabolites and antitumor antibiotics. The efficacy of chemotherapy is often limited by severe side effects, including nausea and vomiting, bone marrow depression, renal damage and central nervous system depression.
Radiation therapy (radiotherapy) relies on the greater ability of normal cells, in contrast to neoplastic cells, to repair themselves after treatment with radiation. Radiotherapy, however, is limited by possible sensitivity of the tissue surrounding the tumor and further by development of resistance thereto.
Surgery involves the bulk removal of diseased (e.g., neoplastic) tissue. When tumor growth is recognized, excision of the tumor mass by surgery is regarded as the therapy of choice. However, during the surgical manipulation, dissemination of malignant tumor cells into the blood and lymph vessels may occur, resulting in metastasis to other body locations and postoperative recurrence resulting in a poor prognosis.
The skin is the largest organ of the body, covering the entire exterior of the body, and includes the epidermis, dermis and subcutaneous layers. Numerous disorders of the skin are known, ranging from those which merely cause discomfort or psychological stress, such as rashes, through benign or cancerous skin lesions, to life-threatening conditions such as skin cancer.
With the increase in the world's ageing population there is a concomitant increase in occurrence of skin disorders that are characterized by skin neoplasia, such as skin lesions and skin cancer, which are often caused by extensive exposure of the skin to ultraviolet beta rays and chemicals in various cosmetic and skin care products. There are several types of skin cancers, the most common being basal cell carcinoma and squamous cell carcinoma, which are both non-melanoma skin cancers.
Basel cell carcinoma develops from abnormal growth of the cells in the lowest layer of the epidermis. Squamous cell cancer involves changes in the squamous cells, found in the middle layer of the epidermis. Malignant melanoma, which occurs in the melanocytes, is less common than squamous or basal cell carcinoma but is much more dangerous. Melanoma is the leading cause of death from skin malignant disease.
Actinic keratosis is a skin condition that sometimes develops into squamous cell carcinoma. Actinic keratosis (also known as a solar keratosis) is a precancerous skin growth usually caused by sun exposure. The most common sites for these lesions are the face, ears, scalp, neck, forearms and hands. Actinic cheilitis is a form of labial mucosa actinic keratosis which occurs on the lips and causes them to become dry, cracked, scaly and pale or white.
Leukoplakia, representing another precursor condition, is manifested by white patches on the tongue or inside the mouth, which have the potential to develop into squamous cell carcinoma.
Benign (non-cancerous) skin tumors may be present at birth, be genetic or develop later. Some benign skin tumors are known to be caused by viruses (for example, warts), systemic disease (for example, xanthelasmas or xanthomas caused by excess cholesterol and fats in the blood), and environmental factors (for example, moles (nevi) and epidermal cysts stimulated by sunlight). Other examples of benign skin tumors are dermatofibromas; angiomas (such as hemangiomas, port-wine stains, lymphangiomas, and pyogenic granulomas); seborrheic keratoses; and acrochordons, or skin tags.
Keratoacanthomas are rapidly growing lesions that occur primarily on sun-exposed skin in older persons. Keratoacanthomas are usually solitary, but multiple lesions may be present. Possible causative agents include ultraviolet light, human papilloma virus, and prolonged contact with coal tar derivatives.
The standard therapy used in benign, pre-malignant and malignant skin tumors is determined by many factors, including the exact hislologic subtype, the tumor size, the growth characteristics and the anatomic location. Treatment is also determined by the previous treatment received, current medical problems and patient's expectations.
Treatment options may be categorized as surgical and non-surgical. Surgical treatments include laser or electrodessication and curettage, simple or wide local excision of the lesion or Mohs micrographic surgery. Non-surgical treatments include radiation therapy, photodynamic therapy, cryotherapy and topical drug therapy.
A surgical treatment of benign, pre-malignant and malignant skin tumors might not be applicable in all patients. The aggressiveness nature of the surgical techniques (as compared to non-surgical procedures) may lead, in some cases, to severe disfigurement due to bony involvement, loss of vision (in cases of tumors located near the eyes) and even death.
Surgical treatment is particularly problematic in treating skin tumors located near the eyes or in the nose region as well as in treating patients suffering from multiple tumors and reoccurrences.
Furthermore, surgical treatment is associated with complications such as bleaching, infections, ulcerations, pain, allergical and exematic reactions, healing problems as well as hypertrophic, kelloidal and painful scars. Such complications often require the administration of additional drugs such as steroids (either topically or systemically), antibiotics, antiseptics, anticoagulants and different kinds of tissue-stimulated creams or drugs, as well as occlusive hydrophilic dressings and laminates (silicon/nylon mesh, collagen, fibrin, etc.).
One of the main concerns when using a surgical procedure for treating skin and mucosal related cancer is the intraoperative dissemination of cancer cells and the subsequent penetration of the cells into blood or lymph vessels. Shedding of cancer cells into the blood and lymph circulation of a patient during surgery is one of the factors of development of postoperative tumor recurrences and distance metastasis associated with a very poor prognosis.
An alternative to surgical treatment is radiation therapy which works by damaging the DNA of cells. Because this therapy is expensive and requires frequent visits over several weeks, it is often not an option for elderly patients with a limited support system. Long term cosmetic results may be poor and the complications of tissue necrosis, chondritis and osteoradionecrosis may occur. Another drawback is the risk of a radiation-induced malignant growth that may occur later, thus radiation is generally not recommended as the primary treatment in patients younger than 50 years of age.
Photodynamic therapy involves the topical administration of photoreactive chemicals and irradiation with light strong enough to activate the chemicals, causing them to emit free radicals and destroy pathologic cells. This therapy is currently limited by its high cost and by persistent skin photosensitivity that lasts weeks.
Cryotherapy is the application of extreme cold to destroy abnormal or diseased tissue. Warts, moles, skin tags, solar keratoses and small skin cancers are candidates for cryosurgical treatment. Disadvantages are the lack of margin control, tissue necrosis, over or under treatment of the tumor, and long recovery time.
Topical drug therapy is limited by superficial basaliomas and actinic keratosis only, to lesions confined to the epidermis. A 5% of 5-fluorouracil (5-FU) cream (Efudex®, Valeant Pharmaceuticals) used in conjugation with topical retinoids may deepen the therapeutic effect and minimize the risk of the disease persisting at the adnexal level but, the treatment is associated with many side effects.
A 5% preparation of Imiquimod cream (Aldara™, 3M Pharmaceuticals), an antiviral agent and as an interferon inducer, applied for 6 weeks has also been shown to eradicate superficial basal cell carcinoma in more than 80% of the cases but the use of imiquimod may be limited by its cost, drug contraindications and side effect. An injection of 5-FU (Adrucil®, Teva Parenteral Medicines, Inc.) or methotrexate Rheumatrex®, DAVA Pharmaceuticals) is primarily limited to lesions whose clinical characteristics and histology are consistent with keratoacanthoma. Intralesional administration of interferon (Roferon-A®, Roche Pharmaceuticals) has been effective for treating basal cell carcinoma but this regimen requires multiple injections for several weeks, is expensive and is associated with flu-like symptoms.
Solcoderm® (Invented by S. Mardi) is an aqueous solution containing organic and inorganic acids in the presence of copper ions. The solution destroys a lesion by tissue mummification. It has been used for the treatment of a variety of benign skin lesions, including solar keratosis, verrucae, condyloma acuminata, hemangiomas and papillomas. The use of Solcoderm in benign skin lesions gives usually good cosmetic results. Solcoderm has also been used in the treatment of malignant lesions including basal and squamous cell carcinoma.
Topical drug treatments of benign, pre-malignant and malignant skin tumors have been also disclosed, for example, in U.S. patent application Ser. Nos. 11/275,258, 11/924,354, 11/506,469, 10/530,723, 10/310,824 and 10/071,124.
Mardi et al. describe a selenium compound of halogenated and polymerized carboxylic acid complex hydrate for treatment of benign, viral, premalignant and malignant non metastasizing pigmented and non-pigmented skin and visible membranous mucosal lesions or tumors [2001; International journal of Immunorehabilitation 3:23-31].
2,2-Dichloropropanoic acid (CH3—CCl2—C(═O)OH; DPA; Dalaphon; CAS No. 75-99-0) is a chemical widely used as a water disinfectant and is also used as an organochloride herbicide as well as a plant growth regulator used to control specific annual and perennial grasses. The major food crop use of DPA is on sugarcane and sugar beets. It is also used on various fruits, potatoes, carrots, asparagus, alfalfa, and flax, as well as in forestry, home gardening, and in or near water to control reed and sedge growth.
The following art describes some of the currently known activities and uses of DPA as a herbicide and water disinfectant: Appl Environ Microbiol. 2003; 69(8):4375-82; Environ Microbiol. 2003; 5(1):48-54; Chem Res Toxicol. 1998 11(11):1332-8; Bull Environ Contam Toxicol. 1990; 45(3):343-9; Radiat Res. 1973; 54(3):388-97; J Agric Food Chem. 1971; 19(1):189-91; Can J Microbiol. 1964; 10:843-52; Appl Microbiol. 1962; 10:206-10; Plant Physiol. 1961; 36(5):698-709; Plant Physiol. 1961; 36(5):688-97; Can J Microbiol. 1959; 5(3):255-60; and Science. 1954; 120(3113):346-347.
DPA is commercially available as its sodium salt or mixed sodium and magnesium salts. In its pure acid form, DPA is a colorless liquid with an acrid odor. As sodium-magnesium salts, it is a white to off-white powder.
DPA has a molecular weight of 142.97 grams/mol; a boiling point of 185-190° C.; a melting point of 20° C.; a relative density of 1.40 (water=1), a solubility in water of 90 g/100 ml at 25° C. and octanol/water partition coefficient of 0.76.
The half-life of DPA in human blood is 1.5-3 days. DPA and all of its known breakdown products dissolve easily in water. They are readily washed from cells and tissues. Because DPA is insoluble in organic solvents and lipids, it does not build up in animal tissues. A non-metabolized form of DPA was excreted in the urine of animals fed the herbicide. Less than 1% of the ingested dose appeared as residues in the milk of dairy cows that were fed DPA. The safety profile of DPA is very good with no observed teratogenic, mitogenic or any other significant systemic adverse effects reported.
Epple and Kirschnick, Leibigs Annalen, 1997, issue 1, pages 81-85, teach oligomerization and polymerization in sodium salts of chlorocarboxylic acids such as sodium 2-chloropropionate, sodium 3-chloropropionate and sodium 2-chlorobutyrate.